α-Catenin interacts with APC to regulate ß-catenin proteolysis and transcriptional repression of Wnt target genes.
Genes Dev
; 27(22): 2473-88, 2013 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-24240237
ABSTRACT
Mutation of the adenomatous polyposis coli (APC) tumor suppressor stabilizes ß-catenin and aberrantly reactivates Wnt/ß-catenin target genes in colon cancer. APC mutants in cancer frequently lack the conserved catenin inhibitory domain (CID), which is essential for ß-catenin proteolysis. Here we show that the APC CID interacts with α-catenin, a Hippo signaling regulator and heterodimeric partner of ß-catenin at cellcell adherens junctions. Importantly, α-catenin promotes ß-catenin ubiquitylation and proteolysis by stabilizing its association with APC and protecting the phosphodegron. Moreover, ß-catenin ubiquitylation requires binding to α-catenin. Multidimensional protein identification technology (MudPIT) proteomics of multiple Wnt regulatory complexes reveals that α-catenin binds with ß-catenin to LEF-1/TCF DNA-binding proteins in Wnt3a signaling cells and recruits APC in a complex with the CtBPCoRESTLSD1 histone H3K4 demethylase to regulate transcription and ß-catenin occupancy at Wnt target genes. Interestingly, tyrosine phosphorylation of α-catenin at Y177 disrupts binding to APC but not ß-catenin and prevents repression of Wnt target genes in transformed cells. Chromatin immunoprecipitation studies further show that α-catenin and APC are recruited with ß-catenin to Wnt response elements in human embryonic stem cells (hESCs). Knockdown of α-catenin in hESCs prevents the switch-off of Wnt/ß-catenin transcription and promotes endodermal differentiation. Our findings indicate a role for α-catenin in the APC destruction complex and at Wnt target genes.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Transdução de Sinais
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Regulação Neoplásica da Expressão Gênica
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Proteína da Polipose Adenomatosa do Colo
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Proteínas Wnt
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Beta Catenina
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Alfa Catenina
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article